A novel agonist of 4-1BB costimulatory receptor shows therapeutic efficacy against a tobacco carcinogen-induced lung cancer.

Abstract

Immunotherapy utilizing checkpoint inhibitors has shown remarkable success in the treatment of cancers. In addition to immune checkpoint inhibitors, immune co-stimulation has the potential to enhance immune activation and destabilize the immunosuppressive tumor microenvironment. CD137, also known as 4-1BB, is one of the potent immune costimulatory receptors that could be targeted for effective immune co-stimulation. The interaction of the 4-1BB receptor with its natural ligand (4-1BBL) generates a strong costimulatory signal for T cell proliferation and survival. 4-1BBL lacks costimulatory activity in soluble form. To obtain co-stimulatory activity in soluble form, a recombinant 4-1BBL protein was generated by fusing the extracellular domains of murine 4-1BBL to a modified version of streptavidin (SA-4-1BBL). Treatment with SA-4-1BBL inhibited the development of lung tumors in A/J mice induced by weekly injections of the tobacco carcinogen NNK for eight weeks. The inhibition was dependent on the presence of T cells and NK cells; depletion of these cells diminished the SA-4-1BBL antitumor protective effect. The number of lung tumor nodules was significantly reduced by the administration of SA-4-1BBL to mice during ongoing exposure to NNK. The data presented in this paper suggest that utilizing an immune checkpoint stimulator as a single agent generate a protective immune response against lung cancer in the presence of a carcinogen. More broadly, this study suggests that immune checkpoint stimulation can be extended to a number of other cancer types, including breast and prostate cancers, for which improved diagnostics can detect disease at the preneoplastic stage.

• Authors: Ayse Ece Gulen, Rakesh Rudraboina, Mohammad Tarique, Vahap Ulker, Haval Shirwan, Esma S Yolcu
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 72 Issue 11 Pg. 3567-3579 (Nov 2023) ISSN: 1432-0851 [Electronic] Germany
• PMID: 37605009 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Carcinogens
• 4-1BB Ligand
• Recombinant Proteins

Topics

• Mice
• Animals
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Tobacco (adverse effects, metabolism)
• Carcinogens (toxicity)
• T-Lymphocytes
• 4-1BB Ligand
• Recombinant Proteins
• Lung Neoplasms (chemically induced)
• Tumor Microenvironment